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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone acetylation is emerging as a major regulatory mechanism thought to modulate gene expression by altering the accessibility of transcription factors to DNA. In this study, treatment of human tumor cells with the histone deacetylase inhibitor, trapoxin (TPX), resulted in selective changes in genes that control the cell cycle. TPX activated p21(waf1) transcription that led to elevated p21(waf1) protein levels in three human tumor cell lines without altering the protein levels of cdk2, cdk4, or cyclin B. In addition, TPX increased cyclin E transcription without increasing the levels of Rb, E2F, dihydrofolate reductase, or glyceraldehyde-3-phosphate dehydrogenase. The elevated levels of p21(waf1) protein led to decreased Rb phosphorylation and cdk2 activity. These effects resulted in G(1) and G(2) cell cycle arrest in H1299 human lung and MDA-MB-435 breast carcinoma cells and apoptosis in A549 lung carcinoma cells. Chromatin immunoprecipitation assays revealed that TPX increased the level of chromatin acetylation associated with histone H3 in the trapoxin-responsive region of the p21(waf1) promoter. This study demonstrates that inhibition of HDAC by TPX increases acetylation of H3-associated chromatin and alters gene expression with marked selectivity.
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PMID:Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects. 1057 69

Histone deacetylases have been described as crucial cofactors of mammalian transcriptional complexes. We have recently identified human histone deacetylase HDAC3 on chromosome 5q31 by fluorescence in situ hybridization (FISH) in a region commonly deleted in malignant myeloid disease. Since HDAC3 carries strong potential to be a tumor suppressor gene, we report herein its exact position between the CD14 and GRIA1 genes within the 5q31.1 subband.
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PMID:High resolution physical mapping of human HDAC3, a potential tumor suppressor gene in the 5q31 region. 1057 14

Histone deacetylases (HDACs) catalyze the removal of acetyl groups on the amino-terminal lysine residues of core nucleosomal histones. This activity is associated generally with transcriptional repression. We have reported previously that inhibition of HDAC activity by hydroxamic acid-based hybrid polar compounds, such as suberoylanilide hydroxamic acid (SAHA), induces differentiation and/or apoptosis of transformed cells in vitro and inhibits tumor growth in vivo. SAHA is a potentially new therapeutic approach to cancer treatment and is in Phase I clinical trials. In several tumor cell lines examined, HDAC inhibitors alter the expression of less than 1% of expressed genes, including the cell cycle kinase inhibitor p21(WAF1). In T24 bladder carcinoma cells, SAHA induces up to a 9-fold increase in p21(WAF1) mRNA and protein, which is, at least in part, because of an increase in the rate of transcription of the gene. SAHA causes an accumulation of acetylated histones H3 and H4 in total cellular chromatin by 2 h, which is maintained through 24 h of culture. An increase in the accumulation of acetylated H3 and H4 was detected throughout the p21(WAF1) promoter and the structural gene after culture with SAHA. The level of histone acetylation did not change in chromatin associated with the actin and p27 genes, and their mRNA expression was not altered during culture of T24 cells with SAHA. Thus, the present findings indicate that the induction of p21(WAF1) by SAHA is regulated, at least in part, by the degree of acetylation of the gene-associated histones and that this induced increase in acetylation is gene selective.
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PMID:Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. 1095 55

The production of heritable changes in gene expression is the driving force in the development and progression of breast cancer. Such changes can result from mutations or from epigenetic events such as hypermethylation of DNA and hypoacetylation of histones. Histone acetylation and DNA methylation are major determinants of chromatin structure, and chromatin structure is a primary regulator of gene transcription. Cancer cells frequently contain both mutated genes and genes with altered expression due to one or more epigenetic mechanisms. This review describes the epigenetic changes that disrupt normal chromatin architecture and modify the expression of key genes in breast cancer cells. The structural integrity of the latter genes is usually intact, but their expression has been substantially altered due to methylation in their promoter region or deacetylation of histones that interact with their promoter region or both mechanisms. Genes affected by epigenetic changes in breast cancers include HoxA5, p21WAF, gelsolin, BRCA1, BRCA2, E-cadherin, steroid hormone receptors, and retinoic acid receptor II. Because these epigenetic modifications are usually reversible by treatment with certain drugs, they represent vulnerabilities in the cancer cell that can be exploited as novel targets for new prevention and therapeutic strategies.
J Mammary Gland Biol Neoplasia 2001 Apr
PMID:Genes, chromatin, and breast cancer: an epigenetic tale. 1150 77

Histone deacetylase inhibitors are potent inducers of growth arrest, differentiation, or apoptotic cell death in a variety of transformed cells in culture and in tumor bearing animals. Histone deacetylases and the family of histone acetyl transferases are involved in determining the acetylation of histones, which play a role in regulation of gene expression. Radiograph crystallographic studies reveal that the histone deacetylase inhibitors, suberoylanilide hydroxamic acid and trichostatin A, fit into the catalytic site of histone deacetylase, which has a tubular structure with a zinc atom at its base. The hydroxamic acid moiety of the inhibitor binds to the zinc. Histone deacetylase inhibitors cause acetylated histones to accumulate in both tumor and peripheral circulating mononuclear cells. Accumulation of acetylated histones has been used as a marker of the biologic activity of the agents. Hydroxamic acid-based histone deacetylase inhibitors limit tumor cell growth in animals with little or no toxicity. These compounds act selectively on genes, altering the transcription of only approximately 2% of expressed genes in cultured tumor cells. A number of proteins other than histones are substrates for histone deacetylases. The role that these other targets play in histone deacetylase inducement of cell growth arrest, differentiation, or apoptotic cell death is not known. This review summarizes the characteristics of a variety of inhibitors of histone deacetylases and their effects on transformed cells in culture and tumor growth in animal models. Several structurally different histone deacetylase inhibitors are in phase I or II clinical trials in patients with cancers.
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PMID:Histone deacetylase inhibitors as new cancer drugs. 1167 88

In order to search the tumor suppressor genes correlated with pathogenesis of human nasopharyngeal carcinoma(NPC), we applied the PCR-based subtractive hybridization technique of representational difference analysis (RDA) to the primary culture cells of normal human nasopharyngeal epithelial and HNE1, a poorly differentiated NPC cell line. Following four successive subtractions of HNE1 complementary DNA from normal human nasopharyngeal epithelial cells complementary DNA, difference products were cloned into pGEM-T easy vector and nucleotide sequences determined. Comparison of cDNA sequences against the databases identified 9 known genes. Known genes included TRIP1(TGF beta receptor interacting protein), TAF, ezrin, MHC II, actinin, Histone H1 zero, Cytokeratin 13, Squalene Synthetase and RNA Synthetase-like. Some of them have an effective suppressive ability on the tumor. In this study, we have demonstrated that cDNA RDA is an effective strategy for systematically isolating differences in gene expression between two related but functionally distinct cells. Our results also indicated that the NPC includes interaction of multigenes and this experiment offers a new route for NPC research.
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PMID:[Differentially expressed cDNA sequences homologous with known genes in human nasopharyngeal carcinoma]. 1193 60

Histone deacetyrase (HDAC) inhibitors induce growth arrest and differentiation of leukemia cell lines and tumor cells derived from a large variety of human tissues. Here we showed that HDAC inhibitors sodium butyrate, TSA, and valproate regulated the expression of Interleukin-18 (IL-18), a cytokine with antitumor and proinflammatory properties, in human acute myeloid leukemia cell lines U937 and HEL. Sodium butyrate increased expression of IL-18 protein and mRNA and activated 1357bp IL-18 gene promoter construct. IL-18 mRNA level was up-regulated by TSA or valproate, which also activated IL-18 full-length promoter. While sodium butyrate or TSA stimulated the 108-bp IL-18 minimal promoter, valproate failed to activate it, indicating that valproate may use a distinct mechanism from sodium butyrate and TSA to activate IL-18 gene expression.
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PMID:Differential effects of histone deacetylase inhibitors on interleukin-18 gene expression in myeloid cells. 1194 5

Histone hypoacetylation and DNA hypermethylation are hallmarks of gene silencing. Although a role for DNA methylation in regulating histone acetylation has been established, it is not clear how and whether epigenetic histone markings influence DNA modifications in transcriptional silencing. We have previously shown that induction of histone acetylation by trichostatin A promotes demethylation of ectopically methylated DNA (Cervoni, N., and Szyf, M. (2001) J. Biol. Chem. 276, 40778-40787). The oncoprotein Set/TAF-Ibeta is a subunit of the recently identified inhibitor of acetyltransferases complex that inhibits histone acetylation by binding to and masking histone acetyltransferase targets (Seo, S. B., McNamara, P., Heo, S., Turner, A., Lane, W. S., and Chakravarti, D. (2001) Cell 104, 119-130). We show here that the overexpression of Set/TAF-Ibeta, whose expression is up-regulated in multiple tumor tissues, inhibits demethylation of ectopically methylated DNA resulting in gene silencing. Overexpression of a mutant Set/TAF-Ibeta that does not inhibit histone acetylation is defective in inhibiting DNA demethylation. Taken together, these results are consistent with a novel regulatory role for Set/TAF-Ibeta, integrating epigenetic states of histones and DNA in gene regulation and provide a new mechanism that can explain how hypermethylation of specific regions might come about by inhibition of demethylation in cancer cells.
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PMID:The oncoprotein Set/TAF-1beta, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing. 1197 94

Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
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PMID:Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 1253 99

The epigenome is defined by DNA methylation patterns and the associated posttranslational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The silencing of gene expression is associated with deacetylated histones, which are often found to be associated with regions of DNA methylation as well as methylation at the lysine 4 residue of histone 3. In contrast, the activation of gene expression is associated with acetylated histones and methylation at the lysine 9 residue of histone 3. The histone deactylases play a major role in keeping the balance between the acetylated and deacetylated states of chromatin. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are similar to the yeast RPD3 protein and localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are homologous to the yeast HDA1 protein and are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are similar to the yeast SIR2 proteins. Since inappropriate silencing of critical genes can result in one or both hits of tumor suppressor gene (TSG) inactivation in cancer, theoretically the reactivation of affected TSGs could have an enormous therapeutic value in preventing and treating cancer. Indeed, several HDAC inhibitors are currently being developed and tested for their potency in cancer chemotherapy. Importantly, these agents are also potentially applicable to chemoprevention if their toxicity can be minimized. Despite the toxic side effects and lack of specificity of some of the inhibitors, progress is being made. With the elucidation of the structures, functions and modes of action of HDACs, finding agents that may be targeted to specific HDACs and potentially reactivate expression of only a defined set of affected genes in cancer will be more attainable.
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PMID:Histone deacetylases: unique players in shaping the epigenetic histone code. 1272 14


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